The present invention relates to oral liquid pharmaceutical mucoadhesive compositions.
Mucoadhesion has been a technology of great interest to pharmaceutical formulators and drug delivery scientists for many years. xe2x80x9cAdhesionxe2x80x9d refers to the relationship between two bodies, an adhesive and a substrate (both existing as condensed phases), when they are held together for an extended period of time by interfacial forces. Patrick R. L.: Introduction. In: Treatise on Adhesion and Adhesives, Volume 1: Theory. R. L. Patrick, Editor Marcel Dekker Inc. New York, 1966, pp. 1-7. An xe2x80x9cadhesivexe2x80x9d is a substance capable of holding materials together by surface attachment. The establishment of an adhesive bond between two materials leads to a reduction in the total surface energy in the system because two free surfaces are replaced by one new surface. xe2x80x9cBioadhesionxe2x80x9d implies that at least one of the surfaces is of biological origin. When the surface is the adherent mucus layer covering one of the mucosal epithelia, such as the inside of the gastrointestinal tract, nasal tract, or vaginal cavity, the term xe2x80x9cmucoadhesionxe2x80x9d is used.
Mucoadhesive materials are useful in a wide variety of applications, particularly in pharmaceutical compositions. Mucoadhesive pharmaceutical compositions can provide prolonged and improved coating and protection of the mouth, esophagus, oropharynx, and/or stomach to inhibit irritation and/or accelerate healing of inflamed or damaged tissue. Furthermore, sustained or prolonged coating provides a matrix to deliver therapeutic agents to mucosal tissues at higher concentrations for higher efficacy, lower side effects, and/or sustained release of the active agent.
Compositions of the present invention are either directly applied to the mucosa or are administered as a per oral liquid suspension. Accordingly, there is a need to identify formulations that successfully and truly adhere to the gastrointestinal mucosa.
Virtually all of the prior art mucoadhesive systems require polymers to provide the mucoadhesive benefit. For example U.S. Pat. No. 5,458,879, Singh et al., issued Oct. 17, 1995, teaches solid dissolvable oral pharmaceutical mucoadhesive vehicle compositions which comprise from about 0.05 to about 20% of a water-soluble mucoadhesive polymer selected from the group consisting of poly(ethylene oxide), poly(ethylene glycol), poly(vinyl alcohol), poly(vinyl pyrrolidine), poly(acrylic acid), poly(hydroxy ethyl methacrylate), hydroxyethyl ethyl cellulose, hydroxy ethyl cellulose and chitosan and mixtures thereof, and also preferably comprise one or more pharmaceutical actives, preferably a cough/cold active, at a level of from about 0.01% to about 50%.
Other references teaching mucoadhesive polymer systems include: EP 526,862, Esposito et al., published Feb. 14, 1996, Vectorpharma; WO 91/06289, Sanvordeker, et al., published May 16, 1991, Watson Labs; U.S. Pat. No. 3,352,752, Puetzer, et al., issued Nov. 14, 1967; WO 92/21325, Fouche, published Dec. 10, 1992, Union Metropolltaine; U.S. Pat. No. 5,225,196, Robinson, issued Jul. 6, 1993, Columbia Laboratories; WO 92/09286, Davis et al., published Jun. 11, 1992, Beecham Group PLC; U.S. Pat. No. 4,427,681, Munshi et al., issued Jan. 24, 1984, RVI; WO 96/20696, Ruddy et al., published Jul. 11, 1996, Eastman Kodak; U.S. Pat. No. 5,858,108, Ruddy et al., issued Dec. 17, 1996, Nanosystems; EP 062,578, Bodin et al., published Jun. 20, 1984, Laboratories Human-Pharm; WO 92/12600, Meignant, published Apr. 10, 1997.
The inventors have surprisingly discovered that certain pharmaceutical materials (titanium dioxide, silicon dioxide, and/or clays) provide mucoadhesive effects. When formulated in certain proportions in aqueous colloidal dispersions with drug actives, and in the form of a flowable liquid, these materials are able to interact with glycoprotein, especially mucin, transforming into a viscous gel, to become effective mucoadhesive systems. This adhesion occurs even though the formulation does not contain any material previously considered to be mucoadhesive, e.g. polymers. These formulations of the present invention provide prolonged and improved coating and protection of the mouth, esophagus, oropharynx, and/or the stomach for relief of irritation, pain and discomfort associated with ailments of the gastrointestinal tract such as laryngopharyngitis (xe2x80x9csore throatxe2x80x9d) and other upper respiratory tract infections/conditions/irritations. Furthermore, these formulations can provide a matrix to deliver an active ingredient in more intimate, concentrated, and sustained contact with the irritated area.
The present invention relates to a mucoretentive pharmaceutical, aqueous liquid composition comprising:
(a) from about 2% to about 50%, by weight of the composition, of colloidal particles selected from the group consisting of silica, titanium dioxide, clay, and mixtures thereof; and
(b) a safe and effective amount of a pharmaceutical active selected from the group consisting of analgesics, decongestants, expectorants, antitussives, antihistamines, bronchodilators, topical anesthetics, sensory agents, oral care agents, miscellaneous respiratory agents, gastrointestinal agents, and mixtures thereof;
wherein the composition has a sedimentation volume ratio of greater than about 0.90 and wherein the triggered viscosity ratio of the composition is at least about 1.2. The present invention further relates to a method of coating the alimentary canal (nasal cavity, oral cavity, esophagus, stomach, and small intestine), in particular to a method of preventing or treating symptoms of upper respiratory tract infections or upper respiratory tract tissue irritation or damage, by administering a safe and effective amount of the above composition.
All percentages and ratios used herein are by weight and all measurements are at room temperature, unless otherwise indicated. As used herein, xe2x80x9cmlxe2x80x9d means milliliter, xe2x80x9cmmxe2x80x9d means millimeter, and xe2x80x9cnmxe2x80x9d means nanometer.